4.1. Therapeutic indications

• Treatment of major depressive disorder.

• Treatment of diabetic peripheral neuropathic pain.

• Treatment of generalised anxiety disorder.

Duloxetine Zentiva is indicated in adults.

For further information see section 5.1.

4.2. Posology and method of administration

Posology

Major depressive disorder

The starting and recommended maintenance dose is 60 mg once daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day have been evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up-titrations.

Therapeutic response is usually seen after 2-4 weeks of treatment.

After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated episodes of major depression, further long-term treatment at a dose of 60 to 120 mg/day could be considered.

Generalised anxiety disorder

The recommended starting dose in patients with generalised anxiety disorder is 30 mg once daily with or without food. In patients with insufficient response the dose should be increased to 60 mg, which is the usual maintenance dose in most patients.

In patients with co-morbid major depressive disorder, the starting and maintenance dose is 60 mg once daily (please see also dosing recommendation above).

Doses up to 120 mg per day have been shown to be efficacious and have been evaluated from a safety perspective in clinical trials. In patients with insufficient response to 60 mg, escalation up to 90 mg or 120 mg may therefore be considered. Dose escalation should be based upon clinical response and tolerability.

After consolidation of the response, it is recommended to continue treatment for several months, in order to avoid relapse.

Diabetic peripheral neuropathic pain

The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above 60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials. The plasma concentration of duloxetine displays large inter-individual variability (see section 5.2). Hence, some patients that respond insufficiently to 60 mg may benefit from a higher dose.

Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely.

The therapeutic benefit should be reassessed regularly (at least every three months) (see section 5.1).

Special populations

Elderly

No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly, especially with duloxetine 120 mg per day for major depressive disorder or generalised anxiety disorder, for which data are limited (see sections 4.4 and 5.2).

Hepatic impairment

Duloxetine Zentiva must not be used in patients with liver disease resulting in hepatic impairment (see sections 4.3 and 5.2).

Renal impairment

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). Duloxetine Zentiva must not be used in patients with severe renal impairment (creatinine clearance <30 ml/min; see section 4.3).

Paediatric population

Duloxetine should not be used in children and adolescents under the age of 18 years for the treatment of major depressive disorder because of safety and efficacy concerns (see sections 4.4, 4.8 and 5.1).

The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder in paediatric patients aged 7-17 years have not been established. Current available data are described in sections 4.8, 5.1 and 5.2.

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has not been studied. No data are available.

Discontinuation of treatment

Abrupt discontinuation should be avoided. When stopping treatment with Duloxetine Zentiva the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration

For oral use.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant use of Duloxetine Zentiva with nonselective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated (see section 4.5).

Liver disease resulting in hepatic impairment (see section 5.2).

Duloxetine Zentiva should not be used in combination with fluvoxamine, ciprofloxacin or enoxacin (i.e. potent CYP1A2 inhibitors) since the combination results in elevated plasma concentrations of duloxetine (see section 4.5).

Severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4).

The initiation of treatment with Duloxetine Zentiva is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).

4.4. Special warnings and precautions for use

Mania and seizures

Duloxetine should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.

Mydriasis

Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing Duloxetine Zentiva to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.

Blood pressure and heart rate

Duloxetine has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing hypertension. Therefore, in patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially during the first month of treatment. Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used with medicinal products that may impair its metabolism (see section 4.5). For patients who experience a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension duloxetine should not be initiated (see section 4.3).

Renal impairment

Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, see section 4.3. See section 4.2 for information on patients with mild or moderate renal dysfunction.

Serotonin syndrome/Neuroleptic malignant syndrome

As with other serotonergic agents, serotonin syndrome or neuroleptic malignant syndrome (NMS), a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs tricyclic antidepressants or triptans), with agents that impair metabolism of serotonin such as MAOIs, with antipsychotics or other dopamine antagonists or with opioids such as buprenorphine (with or without naloxone), tramadol and pethidine that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Serotonin syndrome in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, elevated serum creatine kinase levels, autonomic instability with possible rapid fluctuation of vital signs and mental status changes.

If concomitant treatment with duloxetine and other serotonergic/neuroleptic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

St. John's wort

Adverse reactions may be more common during concomitant use of Duloxetine Zentiva and herbal preparations containing St. John's wort (Hypericum perforatum).

Suicide

Major Depressive Disorder and Generalised Anxiety Disorder

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which duloxetine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.8).

Close supervision of patients and in particular those at high risk should accompany medicinal product therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Diabetic Peripheral Neuropathic Pain

As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Concerning risk factors for suicidality in depression, see above. Physicians should encourage patients to report any distressing thoughts or feelings at any time.

Use in children and adolescents under 18 years of age

Duloxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms (see section 5.1). In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking (see section 4.8).

Haemorrhage

There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs), including duloxetine. Duloxetine may increase the risk of postpartum haemorrhage (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.

Hyponatraemia

Hyponatraemia has been reported when administering duloxetine, including cases with serum sodium lower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly, especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance. Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics.

Discontinuation of treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials adverse events seen on abrupt treatment discontinuation occurred in approximately 45% of patients treated with duloxetine and 23% of patients taking placebo. The risk of withdrawal symptoms seen with SSRI's and SNRI's may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient's needs (see section 4.2).

Elderly

Data on the use of duloxetine 120 mg in elderly patients with major depressive disorder and generalised anxiety disorder are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (see sections 4.2 and 5.2).

Akathisia/psychomotor restlessness

The use of duloxetine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Medicinal products containing duloxetine

Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.

Hepatitis/increased liver enzymes

Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.

Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.

Sucrose

Duloxetine Zentiva gastro-resistant hard capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAOIs)

Due to the risk of serotonin syndrome, duloxetine should not be used in combination with non‑selective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping Duloxetine Zentiva before starting an MAOI (see section 4.3).

The concomitant use of Duloxetine Zentiva with selective, reversible MAOIs, like moclobemide, is not recommended (see section 4.4). The antibiotic linezolid is a reversible non‑selective MAOI and should not be given to patients treated with duloxetine (see section 4.4).

Inhibitors of CYP1A2

Because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUCo-t 6-fold. Therefore Duloxetine Zentiva should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).

CNS medicinal products

The risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described in this section. Consequently, caution is advised when duloxetine is taken in combination with other centrally acting medicinal products or substances, including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Serotonergic agents

In rare cases, serotonin syndrome has been reported in patients using SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if duloxetine is used concomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like moclobemide or linezolid, St. John's wort (Hypericum perforatum) or triptans, buprenorphine, tramadol, pethidine and tryptophan (see section 4.4).

Effect of duloxetine on other medicinal products

Medicinal products metabolised by CYP1A2

The pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).

Medicinal products metabolised by CYP2D6

Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40 mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if duloxetine is co-administered with medicinal products that are predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such as nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).

Oral contraceptives and other steroidal agents

Results of in vitro studies demonstrate that duloxetine does not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not been performed.

Anticoagulants and antiplatelet agents

Caution should be exercised when duloxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when duloxetine was co-administered to patients treated with warfarin. However, concomitant administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

Effects of other medicinal products on duloxetine

Antacids and H2 antagonists

Co-administration of duloxetine with aluminium- and magnesium-containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.

Inducers of CYP1A2

Population pharmacokinetic analyses have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.

4.6. Fertility, pregnancy and lactation

Fertility

In animal studies, duloxetine had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity.

Pregnancy

Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure (see section 5.3).

Two large observational studies do not suggest an overall increased risk of major congenital malformation (one from the US including 2,500 exposed to duloxetine during the first trimester and one from the EU including 1,500 exposed to duloxetine during the first trimester). The analysis on specific malformations such as cardiac malformations shows inconclusive results.

In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks gestational age to delivery) was associated with an increased risk for preterm birth (less than 2-fold, corresponding to approximately 6 additional premature births per 100 women treated with duloxetine late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association was not seen in the US study.

The US observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following duloxetine exposure within the month prior to birth.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth.

Duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.

Breast-feeding

Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did not breast feed their children. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the use of duloxetine while breast-feeding is not recommended.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Duloxetine may be associated with sedation and dizziness. Patients should be instructed that if they experience sedation or dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in patients treated with duloxetine were nausea, headache, dry mouth, somnolence, and dizziness. However, the majority of common adverse reactions were mild to moderate, they usually started early in therapy, and most tended to subside even as therapy was continued.

Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials.

Table 1: Adverse reactions

Frequency estimate: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

Laryngitis

Immune system disorders

Anaphylactic reaction

Hypersensitivity disorder

Endocrine disorders

Hypothyroidism

Metabolism and nutrition disorders

Decreased appetite

Hyperglycaemia (reported especially in diabetic patients)

Dehydration

Hyponatraemia

SIADH6

Psychiatric disorders

Insomnia

Agitation

Libido decreased

Anxiety

Orgasm abnormal

Abnormal dreams

Suicidal ideation5,7

Sleep disorder

Bruxism

Disorientation

Apathy

Suicidal behaviour5,7

Mania

Hallucinations

Aggression and anger4

Nervous system disorders

Headache

Somnolence

Dizziness

Lethargy

Tremor

Paraesthesia

Myoclonus

Akathisia7

Nervousness

Disturbance in attention

Dysgeusia

Dyskinesia

Restless legs syndrome

Poor quality sleep

Serotonin syndrome6

Convulsion1

Psychomotor restlessness6

Extra-pyramidal symptoms6

Eye disorders

Blurred vision

Mydriasis

Visual impairment

Glaucoma

Ear and labyrinth disorders

Tinnitus1

Vertigo

Ear pain

Cardiac disorders

Palpitations

Tachycardia

Supraventricular arrhythmia, mainly atrial fibrillation

Stress cardiomyopathy (Takotsubo cardiomyopathy)

Vascular disorders

Blood pressure increase3

Flushing

Syncope2

Hypertension3,7

Orthostatic hypotension2

Peripheral coldness

Hypertensive crisis3,6

Respiratory, thoracic and mediastinal disorders

Yawning

Throat tightness

Epistaxis

Interstitial lung disease10

Eosinophilic pneumonia6

Gastrointestinal disorders

Nausea

Dry mouth

Constipation

Diarrhoea

Abdominal pain

Vomiting

Dyspepsia

Flatulence

Gastrointestinal haemorrhage7

Gastroenteritis

Eructation

Gastritis

Dysphagia

Stomatitis

Haematochezia

Breath odour

Microscopic colitis9

Hepato-biliary disorders

Hepatitis3

Elevated liver enzymes (ALT, AST, alkaline phosphatase)

Acute liver injury

Hepatic failure6

Jaundice6

Skin and subcutaneous tissue disorders

Sweating increased

Rash

Night sweats

Urticaria

Dermatitis contact

Cold sweat

Photosensitivity reactions

Increased tendency to bruise

Stevens-Johnson Syndrome6

Angio-neurotic oedema6

Cutaneous vasculitis

Musculoskeletal and connective tissue disorders

Musculo-skeletal pain

Muscle spasm

Muscle tightness

Muscle twitching

Trismus

Renal and urinary disorders

Dysuria

Pollakiuria

Urinary retention

Urinary hesitation

Nocturia

Polyuria

Urine flow decreased

Urine odour abnormal

Reproductive system and breast disorders

Erectile dysfunction

Ejaculation disorder

Ejaculation delayed

Gynaecological haemorrhage

Menstrual disorder

Sexual dysfunction

Testicular pain

Menopausal symptoms

Galactorrhoea

Hyperprolactinaemia

Postpartum haemorrhage6

General disorders and administration site conditions

Falls8

Fatigue

Chest pain7

Feeling abnormal

Feeling cold

Thirst

Chills

Malaise

Feeling hot

Gait disturbance

Investigations

Weight decrease

Weight increase

Blood creatine phosphokinase increased

Blood potassium increased

Blood cholesterol increased

1 Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.

2 Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.

3 See section 4.4.

4 Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.

5 Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4).

6 Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.

7 Not statistically significantly different from placebo.

8 Falls were more common in the elderly (≥ 65 years old)

9 Estimated frequency based on all clinical trial data.

10Estimated frequency based on placebo-controlled clinical trials.

Description of selected adverse reactions

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.

Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care group.

The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-treated and placebo-treated patients.

Paediatric population

A total of 509 paediatric patients aged 7 to 17 years with major depressive disorder and 241 paediatric patients aged 7 to 17 years with generalised anxiety disorder were treated with duloxetine in clinical trials. In general, the adverse reaction profile of duloxetine in children and adolescents was similar to that seen for adults.

A total of 467 paediatric patients initially randomized to duloxetine in clinical trials experienced a 0.1 kg mean decrease in weight at 10-weeks compared with a 0.9 kg mean increase in 353 placebo-treated patients. Subsequently, over the four- to six-month extension period, patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and gender-matched peers.

In studies of up to 9 months an overall mean decrease of 1% in height percentile (decrease of 2% in children (7-11 years) and increase of 0.3% in adolescents (12-17 years)) was observed in duloxetine- treated paediatric patients (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1,000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.